PITCH-HF will be the first trial to assess the effect of a selective pulmonary vasodilator, the type 5 phosphodiesterase (PDE5) inhibitor tadalafil, on long-term clinical outcomes in heart failure (HF) patients with left ventricular (LV) systolic dysfunction (LVSD) and secondary pulmonary hypertension (PH). LVSD patients with secondary PH and right ventricular (RV) dysfunction constitute a high-risk subpopulation of HF with increased morbidity and mortality. However, current guideline-based therapy focuses on the treatment of LV dysfunction. Placebo-controlled studies of PDE5 inhibition in this population have demonstrated improvements in the prognostic markers of exercise capacity and quality of life and provide the basis for a multicenter trial of the effect of tadalafil on HF morbidity and mortality. Three Aims address: (1) Time to the primary endpoint (cardiovascular (CV) mortality or HF hospitalization) and secondary endpoints (time to CV mortality, HF hospitalization, all-cause mortality; and frequency of CV/HF hospitalizations); (2) Changes in functional capacity (6-minute walk distance) and quality of life (Minnesota Living with HF questionnaire), from baseline to 3 and 18 months; and (3) Establishment of a plasma samples repository (baseline, 3, 18 months) for ancillary studies of potential biomarkers that may predict beneficial responses to PDE5 inhibition. The CCC (Massachusetts General Hospital, PI: Marc Semigran MD) and the DCC (New England Research Institutes, PIs: Rebecca Li PhD; Susan Assmann PhD) provide extensive complementary expertise and experience to ensure trial success. Study drug, valued at [$54 million], as well as support for the Drug Distribution Center, will be provided as an in-kid gift by [Eli Lilly Inc.] Recruiting 100 certified sites (US and Canada) in year 1, PITCH-HF will enroll 2,102 subjects in years 2-4 and follow them for an average of 2.5 years of treatment. [Feasibility has been demonstrated in a pilot study conducted at selected sites. 82 site commitments have been obtained to-date.] The trial will have 85% power to detect a 20% relative reduction in the 2.5-year rate for the primary outcome (from 30% to 24%) with a = 0.05 and subject attrition rates of up to 15%. Primary analyses will be intention-to-treat, using Cox regression models and analysis of covariance as appropriate. Three interim analyses are proposed. The patient population includes: Adults e21 years; NYHA Class II-IV HF with LVSD (LVEF < 40%); and either: an episode of decompensated HF within 12 months, or plasma BNP level e300 pg/ml or NT-proBNP e1800pg/ml measured within 3 months. All patients must have documented secondary PH within 6 months, and be on stable guideline-based medical therapy. African-Americans intolerant of combined isosorbide dinitrate/hydralazine therapy may be enrolled. The results of this seminal trial, if positive, will provide a new, effective therapy fo a substantive segment of HF patients that has a high morbidity and mortality. If negative, it will deter the use of PDE5 inhibitors in systolic HF and will motivate further investigation into other potential therapies for RV dysfunction in HF patients.